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Five Key Considerations for Writing First-in-Human Protocols Under EMA Guidelines

Five Key Considerations for Writing First-in-Human Protocols Under EMA Guidelines

1 August 2018

As pharmaceuticals move from animal to first-in-human (FIH) clinical trials, establishing appropriate strategies to minimise risk in early phase clinical trials is necessary and should be a priority for the safety and wellness of clinical trial participants, whether patients or healthy volunteers. The goal of FIH clinical trials is to study the human pharmacology, tolerability and safety of pharmaceuticals to compare how effects seen in non-clinical studies translate into humans. To further improve strategies to identify and mitigate risks for trial participants, the European Medicines Agency implemented an updated guidance in February 2018. The Guidance on Strategies to Identify and Mitigate Risks for First in Human and Early Clinical Trials with Investigational Medicinal Products addresses the important issues needing consideration during the study design process.

Traditionally, FIH clinical trials were mostly associated with a single ascending dose (SAD) design, and then followed by a multiple ascending dose (MAD) clinical trial. Yet, with the emerging integration of pharmacokinetic (PK), pharmacodynamic (PD), and human safety data during trials, there has been an increase in performing early phase clinical trials with integrated protocols that combine different study parts.

Adopting a strategic early phase study design can help mitigate risks, and accelerate drug approval and time to market.

Key Aspects in Study Planning

An early phase clinical trial study design will optimise knowledge gained from the study, while ensuring the safety of participants. By collecting more data and information about a drug’s potential risks in early phase studies – rather than racing through regulatory hurdles – sponsors could increase R&D success later.

Here are some key considerations:

Choice of study population. There are many factors to consider when deciding whether to use healthy volunteers or patients. The risks of enroling healthy volunteers versus patients must be weighed including toxicities, PK variability, lifestyle conditions, benefits to patients and special populations. Studies with healthy volunteers must have inclusion/exclusion criteria that require vital signs, ECGs, and clinical laboratory assessments to be normal. Furthermore, protocols should describe the exact nature of assessments, including timing and anticipated changes to assessments. Protocols must also define the length of subject follow-up and detail how subjects with abnormal findings will be followed after the end of the study period. Monitoring for safety effects must take into consideration PD effects, not just PK profile data.

Careful dose selection. Protocols needs to outline and explain the estimated initial drug dose, maximum dose exposure and subsequent dose escalation steps. Also, all available non-clinical information, such as toxicology profiles, should be taken into consideration for starting doses, dose escalation and maximum exposure in early phase clinical trials. Moreover, clinical data, such as PK, PD and adverse event reports, occurring during the trial will need to be considered. Additionally, protocols should describe the decision-making criteria for adapting dosage based on clinical data collected during the trial. Lastly, for FIH trials, sentinel dosing of two subjects (one active, one placebo) is required, at minimum, for the first SAD and MAD cohorts.

Detail integrated protocols. Due to the complexity of integrated protocols – in which multiple objectives are investigated within the same clinical trial – their review can be more complicated and time-consuming. The criteria to move from one part of a study, such as SAD to MAD, must be defined. While it is acceptable to overlap SAD and MAD portions of a trial, it is necessary for the expected exposure to already have been evaluated in a SAD cohort prior to being evaluated in a MAD cohort. Moreover, food effect studies can be conducted in parallel with the SAD, provided the dose level in the food effect trial has been evaluated in a prior SAD cohort. Drug-drug interaction studies should not be integrated into FIH and dose escalation protocols unless there is a need that requires a specific concomitant medication in the initial patient studies.

Define stopping rules. FIH and dose escalation protocols must define stopping rules for individuals, cohorts, dose escalation and the entire study. Rules must specify whether the rule is a temporary stop for further evaluation, or a final end to dosing for the study. Furthermore, studies with healthy volunteers must include precaution in the event of the following:

A serious adverse reaction in one subject

Severe non-serious adverse reactions in two subjects in the same cohort, independent of within or not within the same system-organ-class

Choice of trial sites. Pick appropriate clinical facilities conducted by investigators and staff with the necessary training and experience in early phase clinical trials. It is a necessity for FIH clinical trials to take place under controlled conditions with close supervision of trial participants during and after dosing. Sites must have access to emergency supplies, and staff must be prepared for medical emergencies. While FIH studies should be conducted at a single site, if multiple sites are required for enrolment, protocols should include a description of measures to reduce risks that might occur from the use of multiple sites.

A well-designed, robust early phase study strategy can help you minimise risk for trial participants and avoid further drug development challenges that frequently cause added study costs and delayed timelines. By partnering with a CRO, early phase experts can assist in designing an effective and comprehensive early phase study strategy to help accelerate product approval and market entry by identifying and addressing safety and regulatory issues early on.